In December 2019, the Wuhan Municipal Health Committee (Hubei province, China) informed about an outbreak of viral pneumonia of unknown etiology. A new RNA virus from the family Coronaviridae (SARS-CoV-2) was identified as the causative agent of the human disease designated COVID-19. From then onwards, more than 130,000 confirmed cases and almost 5,000 deaths have been reported in 122 countries. Prevention of healthcare professionals’ infection is crucial for the management of a pandemic such as COVID-19. Pre-exposure prophylaxis (PrEP) has already demonstrated to be useful in treating healthcare contacts of other diseases, but this has not been evaluated for preventing COVID-19 yet. Since hydroxychloroquine has been observed to effectively inhibit SARS-CoV-2 in vitro, we aim to evaluate the clinical use of hydroxychloroquine in PEP in high-risk healthcare workers to reduce SARS-CoV-2 infection in a unicentric, double-blinded, randomized, controlled clinical trial.